With regard to their analgesic effects, opioids have been thought to act on receptors within the central nervous system exclusively. Recently, however, we have shown that, within inflamed rat paws, immune-cell derived opioid peptides can activate peripheral opioid receptors located on sensory nerves and induce antinociception. The purpose of our current research is to examine agents for their capability of releasing opioid peptides from immune cells and for their potential in the inhibition of pain. Such peripheral effects are of considerable interest in view of the avoidance of centrally mediated side effects of opioid analgesics, such as dysphoria, dependence, addiction, sedation and respiratory depression. Our most recent experiments have examined whether corticotropin releasing factor (CRF) or interleukin-1Beta (IL-1Beta) release opioid peptides in inflamed tissue and result in analgesia. Upon administration of CRF or IL-1Beta into both paws of rats with unilateral hindpaw inflammation, nociceptive thresholds increase markedly in the inflamed but not in the noninflamed paw. Alpha-helical-CRF and interleukin-1 receptor antagonist, respectively, antagonize this analgesic effect, indicating that CRF and IL-1Beta act via their specific receptors. These receptors are most likely localized on immune cells within the inflamed tissue because immunosuppression by cyclosporin A attenuates the effect. In experiments with antisera against opioid peptides we have shown that endogenous opioids released from immune cells mediate these analgesic effects. This is supported by the fact that naloxone and other opioid antagonists reverse these effects. These results suggest that CRF and IL-1Beta, by activation of their receptors on immune cells, cause a release of opioids which subsequently occupy their receptors on sensory nerves resulting in inhibition of pain. Ongoing in vitro experiments examine whether CRF or IL-1Beta are capable of releasing endorphin in cell suspensions prepared from inflamed and noninflamed lymph nodes and whether this release can be attenuated by the respective antagonists. To further elucidate the mechanisms governing the apparent "upregulation" of opioid receptors on sensory nerves during inflammation, we are examining the permeability of the perineurial barrier by histochemistry and the expression of opioid receptor genes in dorsal root ganglia.